Tingyu Li

Antioxidant vitamin status during pregnancy in relation to cognitive development in the first two years of life

OBJECTIVE To investigate the correlation of the antioxidant vitamins status (vitamins A, E and C) during pregnancy and the intellectual development of early childhood. METHOD A total of 150 paired maternal-neonatal subjects were recruited into the present study. The serum concentrations of antioxidant vitamins (vitamins A, E and C) in maternal blood and cord blood after delivery were determined by high performance liquid chromatography and the intellectual development was evaluated by Gesell Development Schedules (GDS) at two-years-old. RESULT Children with higher cord serum vitamin E level showed higher scores of motor, adaptive domain and average compared to children with lower cord serum vitamin E level (p<0.01 or 0.05), respectively. Cord serum vitamin A level had significant positive correlation with effect on motor DQs (beta=4.227, p<0.05), and vitamin E level in cord blood showed a positive relation with motor DQ and average DQ (beta=0.329 and 0.1875, respectively, p<0.05) in multiple linear regression model. The language and social DQs were influenced by placental vitamin E transport rate (beta=3.1968 and 3.0194, respectively, p<0.05). The placental transport rate of vitamin E also was a protective factor for the prevalence of motor behavior developmental delay [OR: 0.118, 95% confident interval (95% CI), 0.018-0.765, p=0.0251], personal and social behavior developmental delay (OR: 0.052, 95% CI: 0.004-0.610, p=0.0185) and average developmental delay (OR: 0.041, 95% CI: 0.003-0.642, p=0.0229) in logistic multiple regression model. CONCLUSION Data suggested that vitamin A, E status and vitamin E transfer rate at delivery had beneficial influence on childrens cognitive and behavior development quotients.

The genetic variability of glycoproteins among respiratory syncytial virus subtype A in China between 2009 and 2013

Human respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections in infants and children under 5years of age. The novel genotype ON1 has a 72-nucleotide duplication, which is the largest duplicated genome portion of RSV. Whether the ON1 genotype will follow the pattern of the BA genotype, which has a 60-nucleotide duplication, and become the predominant RSV-A strain is a global concern. To obtain information regarding the prevalence of the ON1 genotype in Chongqing in Southwestern China, we examined the circulation pattern of RSV-A identified over four consecutive years (June 2009 to August 2013). In this study, 312 (12%) RSV-A strains were isolated from 2601 nasopharyngeal aspirates, and partial G gene was sequenced successfully in 250 isolates. Of the sequenced Chongqing RSV-A isolates, 237 (94.8%) strains were the NA1 genotype, 4 (1.6%) strains were the NA3 genotype, 4 (1.6%) strains were the NA4 genotype, 1 (0.4%) strain was the GA1 genotype, and 4 (1.6%) strains were identified as the ON1 genotype. Analysis of the distribution, phylogeny, and evolution of the ON1 strains that were collected globally until December 2013 revealed that the ON1 genotype has rapidly disseminated across the world under positive selection pressures. Future studies will determine whether this new genotype will continue to spread and become the dominant strain of RSV-A worldwide. These findings may contribute to the understanding of RSV evolution and to the potential development of a vaccine against RSV.

Retinoic acid receptor beta mediates all-trans retinoic acid facilitation of mesenchymal stem cells neuronal differentiation.

All-trans retinoic acid plays an important role in nervous system development. However, the effects of all-trans retinoic acid on the neuronal differentiation of mesenchymal stem cells and the mechanisms through which this differentiation takes place are still poorly understood. Here, we investigated the biological effects of all-trans retinoic acid on the neuronal differentiation of mesenchymal stem cells and the signaling pathways that mediated these effects. We found that the neuronal differentiation efficiency of mesenchymal stem cells following all-trans retinoic acid pre-induction was greater and the axonal length was longer than was observed with mesenchymal stem cells that were not pre-induced. mRNA and protein levels of the neural-markers Nestin, NSE, MAP-2, Tau and Tuj1 were stronger in neural-like cells derived from all-trans retinoic acid-pretreated mesenchymal stem cells than in those not pre-induction. Interestingly, the neuronal excitability of differentiated neural-like cells exhibited the same patterns between these two groups. Clear expression of retinoic acid receptor alpha and gamma in mesenchymal stem cells was observed, while retinoic acid receptor beta was barely detected. However, retinoic acid receptor beta expression in mesenchymal stem cells after neuronal induction increased dramatically, in contrast with retinoic acid receptor alpha and gamma expression, and retinoic acid receptor beta expression in mesenchymal stem cells receiving all-trans retinoic acid pre-induction was even stronger. Next, retinoic acid receptor alpha, beta and gamma were over-expressed by recombinant adenovirus infection prior to neuronal induction. Retinoic acid receptor alpha and gamma over-expression did not impact the neuronal differentiation of mesenchymal stem cells. However, retinoic acid receptor beta over-expression promoted neuronal differentiation to a similar level as observed following all-trans retinoic acid pre-induction. The neuronal differentiation promoting effects of all-trans retinoic acid on mesenchymal stem cells could be inhibited by siRNA silencing of retinoic acid receptor beta and by LE135, an inhibitor of retinoic acid receptor beta. Taken together, these results suggest that all-trans retinoic acid pre-induction facilitates the neuronal differentiation of mesenchymal stem cells. These facilitation effects are achieved by activating the retinoic acid receptor beta signaling pathway.

Immortalized mesenchymal stem cells: an alternative to primary mesenchymal stem cells in neuronal differentiation and neuroregeneration associated studies

BackgroundMesenchymal stem cells (MSCs) can be induced to differentiate into neuronal cells under appropriate cellular conditions and transplanted in brain injury and neurodegenerative diseases animal models for neuroregeneration studies. In contrast to the embryonic stem cells (ESCs), MSCs are easily subject to aging and senescence because of their finite ability of self-renewal. MSCs senescence seriously affected theirs application prospects as a promising tool for cell-based regenerative medicine and tissue engineering. In the present study, we established a reversible immortalized mesenchymal stem cells (IMSCs) line by using SSR#69 retrovirus expressing simian virus 40 large T (SV40T) antigen as an alternative to primary MSCs.MethodsThe retroviral vector SSR#69 expressing simian virus 40 large T (SV40T) antigen was used to construct IMSCs. IMSCs were identified by flow cytometry to detect cell surface makers. To investigate proliferation and differentiation potential of IMSCs, cell growth curve determination and mesodermal trilineage differentiation tests were performed. Neuronal differentiation characteristics of IMSCs were detected in vitro. Before IMSCs transplantation, we excluded its tumorigenicity in nude mice firstly. The Morris water maze tests and shuttle box tests were performed five weeks after HIBD models received cells transplantation therapy.ResultsIn this study, reversible IMSCs were constructed successfully and had the similar morphology and cell surface makers as primary MSCs. IMSCs possessed better ability of proliferation and anti-senescence compared with primary MSCs, while maintained multilineage differentiation capacity. Neural-like cells derived from IMSCs had similar expressions of neural-specific genes, protein expression patterns and resting membrane potential (RMP) compared with their counterparts derived from primary MSCs. There was no bump formation in nude mice subcutaneously injected with IMSCs. IMSCs played same role as primary MSCs to improve learning ability and spatial memory of HIBD rats.ConclusionsIMSCs not only retain their features of primary MSCs but also possess the ability of high proliferation and anti-senescence. IMSCs can definitely be induced to differentiate into neuronal cells in vitro and take the place of primary MSCs for cell transplantation therapy without tumorigenesis in vivo. The stable cell line is particularly useful and valuable as an alternative to MSCs in neuronal differentiation and neuroregeneration associated studies.

Correlation between Nutrition and Symptoms: Nutritional Survey of Children with Autism Spectrum Disorder in Chongqing, China.

Restricted diets and inadequate nutrient intake of children with autism spectrum disorder (ASD) have been reported. This study examined the nutritional statuses of children with ASD and the relationships between their behaviors and nutritional intake. A total of 154 children with ASD (age = 5.21 ± 1.83 years) and 73 typically-developing (TD) children (age = 4.83 ± 0.84 years) from Chongqing, China, were enrolled. The severity of ASD was evaluated using the Childhood Autism Rating Scale (CARS). The serum ferritin, folate, vitamin B12, 25(OH) vitamin D, and vitamin A concentrations in the children with ASD were determined. All participants underwent anthropometric examinations, dietary assessments, and questionnaire assessments about their feeding behaviors, and gastrointestinal symptoms. The ZHA, ZWA, and ZBMIA were found to be significantly lower in the children with ASD compared with those without ASD. In addition, the percentages of children exhibiting severe picky eating and severe resistance to new foods, as well as those with a reported general impression of severe eating problems and constipation, were higher among the children with ASD. These children consumed significantly fewer macronutrients compared with the children without ASD. In addition, the children with ASD had the highest rate of vitamin A deficiency, followed by iron deficiency. After adjusting for sex, the vitamin A concentration was found to be negatively correlated with the CARS score (rs = −0.222, p = 0.021). No correlation between the ferritin, folate, vitamin D, or vitamin B12 concentration and the CARS score was found. These results suggest that reduced macronutrient intakes, severe feeding behavior issues, constipation, and vitamin A deficiency are quite common among children with ASD. Further, a low serum vitamin A level may be a risk factor for symptoms of ASD. However, the underlying mechanism should be further studied.

Impact of Human Rhinovirus Types and Viral Load on the Severity of Illness in Hospitalized Children With Lower Respiratory Tract Infections.

Background: Human rhinovirus (HRV) is not only responsible for at least one-half of all common colds but also associated with bronchitis, bronchiolitis, pneumonia and acute asthma exacerbation. However, the impact of different HRV types and viral load on disease severity has not been thoroughly elucidated. Methods: From January 2012 to September 2014, 1742 nasopharyngeal aspirate specimens from hospitalized children with lower respiratory tract infections were analyzed by quantitative HRV-specific real-time polymerase chain reaction. Results: Among these 1742 children, HRV (407/1742, 23%) was the second most common viral agent after respiratory syncytial virus. HRV-A, HRV-B, HRV-C and HRV untyped were detected in 229 (56%), 27 (7%), 100 (25%) and 51 (13%) specimens, respectively. Children except who experienced wheezing were more common in the HRV-C detection group than in the HRV-A detection group; there were no other significant differences between the 2 groups, including the percent of children diagnosed with severe diseases. Logistic regression models demonstrated that there was no difference in disease severity among HRV types. In HRV-A detection group, in children younger than 2 years, the viral load was higher in the severe group than in the nonsevere group; but in the HRV-C detection group, there was no difference. Conclusions: HRV was frequently present in hospitalized children with lower respiratory tract infections in Chongqing, China. The disease severity for HRV-C and HRV-A was similar. A high load of HRV-A in the lower respiratory tract might be connected with disease severity in children younger than 2 years.

Co-assessment of iron, vitamin A and growth status to investigate anemia in preschool children in suburb Chongqing, China

BackgroundAnemia is a widespread public health problem, which is due to many factors, nutritional or non-nutritional. Iron, vitamin A and growth status were assessed to investigate anemia of preschool children in suburb Chongqing, China.MethodsA descriptive, cross-sectional survey was performed on 459 preschool children aged 2 to 7 years randomly chosen from the kindergartens in 6 suburban districts of Chongqing. Weight and height levels, hemoglobin, erythrocyte protoporphyrin, serum retinol, and ferritin concentrations were measured to evaluate the anthropometric and nutritional status.ResultsThe rates of stunt, underweight, overweight, wasting, obesity, anemia, iron deficiency, vitamin A deficiency (VAD), and marginal VAD were 6.3%, 3.9%, 3.7%, 1.5%, 3.1%, 23.5%, 15.0%, 6.3% and 25.9%, respectively. Serum retinol concentration was significantly lower in children with anemia than in those without anemia (P=0.003), and the retinol concentration was associated with hemoglobin (Pearson’s correlation coefficient, r=0.22, P<0.01). Children with VAD had a significantly increased risk for anemia (odds ratio, 2.56; 95% confident interval, 1.15–5.70). In all 108 children with anemia, only 42 were related to VAD and 12 related to iron deficiency, suggesting that almost half of the anemia children cannot be explained solely by iron deficiency or VAD.ConclusionsVitamin A and iron deficiency are still public health problems in some localities of China. Public health interventions in anemia control should be used to eliminate deficiencies of vitamin A, iron, and other micronutrients by deliberate supplementation. Attention must be paid to such deficiencies in high-risk groups, especially in preschool children.

Vitamin A Deficiency Impairs Spatial Learning and Memory: The Mechanism of Abnormal CBP-Dependent Histone Acetylation Regulated by Retinoic Acid Receptor Alpha

Vitamin A (VA) is an essential micronutrient. Numerous studies have confirmed that VA deficiency (VAD) leads to a decline in learning and memory function. Our previous studies have demonstrated that retinoic acid nuclear receptor α (RARα) in the hippocampus plays a crucial role in learning and memory, but the exact mechanism for this process is unclear. Epigenetic modifications, particularly histone acetylation, are involved in nervous system development, learning and memory function, and the pathogenesis of neurodegenerative diseases. Histone acetyltransferases (HATs), such as CREB-binding protein (CBP), E1A-binding protein p300 (p300), and p300/CBP-associated factor (PCAF), are critical for regulating memory function. The current study uses RARα and CBP as examples to study the connections between the RA signaling pathway and histone acetylation modification and to reveal the epigenetic mechanism in VAD-induced learning and memory impairment. This study examined the expression of RARα, HATs, acetylated histone H3/H4, and memory-related genes (Zif268, cFos, FosB), as well as the interaction of RARα and CBP in the hippocampus of 8-week-old rats. Additionally, the changes shown in vivo were further assessed in primary cultured neurons with the inhibition or overexpression of RARα. We found significantly lower levels of histone acetylation in the VAD rats. Furthermore, this downregulation, which impairs learning and memory, is induced by the dysregulation of CBP-dependent histone acetylation that is mediated by RARα. This work provides a solid theoretical foundation and experimental basis for the importance of ensuring sufficient nutritional VA during pregnancy and early life to prevent impairments of learning and memory in adulthood.

Perinatal vitamin A status in relation to neurodevelopmental outcome at two years of age.

UNLABELLED Information about the effect of antioxidant vitamins nutrition during pregnancy on offsprings intellectual development is extremely limited. OBJECTIVE To investigate the correlation of antioxidant vitamins (Vitamin A, E and C) at delivery and the neurodevelopment of early childhood. METHOD A total of 158 paired maternal-neonatal subjects were recruited. The serum concentrations of vitamin A, E and C in maternal and cord blood after delivery were determined and intellectual development was evaluated by Gesell Development Schedule (GDS) at two years old. RESULT After adjusting for potential confounders, vitamin A placental transport ratio (VA-PTR) was positively associated with motor area development quotients (DQ) and average DQ(p<0.01). Cord VA level was positively related with language area and social area DQ (p<0.05). Nevertheless, there was no significant association between cord VE, VC levels, VE PTR or VC PTR and GDS. The adaptive area and average DQ in high cord VA group was higher than those in low VA group (p<0.05). Cord VA level and VA-PTR were positively associated with birth head circumference and birth weight, respectively. CONCLUSION Our data suggested that adequate vitamin A at delivery had beneficial influence on neonatal birth outcomes and childrens neurodevelopment in later childhood.

AP2α transcriptional activity is essential for retinoid-induced neuronal differentiation of mesenchymal stem cells

Pre-activation of the retinoid signaling pathway by all-trans retinoic acid facilitates neuronal differentiation of mesenchymal stem cells. Using protein/DNA based screening assays, we identified activator protein 2α as an important downstream target of all-trans retinoic acid. Although all-trans retinoic acid treatment significantly increased activator protein 2α transcriptional activity, it did not affect its expression. Inhibition of activator protein 2α with dominant-negative mutants reduced ATRA-induced differentiation of mesenchymal stem cells into neurons and reversed its associated functional recovery of memory impairment in the cell-based treatment of a hypoxic-ischemic brain damage rat model. Dominant-negative mutants of activator protein 2α inhibited the expression of neuronal markers which were induced by retinoic acid receptor β activation. All-trans retinoic acid treatment increased phosphorylation of activator protein 2α and resulted in its nuclear translocation. This was blocked by siRNA-mediated knockdown of retinoic acid receptor β. Furthermore, we found that retinoic acid receptor β directly interacted with activator protein 2α. In summary, the regulation of all-trans retinoic acid on activator protein 2α transcriptional activity was mediated by activation of retinoic acid receptor β and subsequent phosphorylation and nuclear translocation of activator protein 2α. Our results strongly suggest that activator protein 2α transcriptional activity is essential for all-trans retinoic acid-induced neuronal differentiation of mesenchymal stem cells.